JP6882538B2 - Composition for injection - Google Patents

Description

The present disclosure is (s) -4 ((5,7-difluorochroman-4-yl) oxy) -N, N-2-trimethyl-1H-benzo [d] imidazole-6-carboxamide or pharmaceutically acceptable thereof. The present invention relates to an injectable composition containing a salt thereof and a method for producing the same.

(S) -4 ((5,7-difluorochroman-4-yl) oxy) -N, N-2-trimethyl-1H-benzo [d] imidazole-6-carboxamide represented by the following formula 1 is It is a pharmaceutically active ingredient having a molecular weight of 387.39.

[Equation 1]

The compound is a pharmaceutical ingredient used to prevent and treat diseases mediated by acid pump antagonism and (but not limited to) gastroesophageal disorders such as gastroesophageal reflux disease, peptic ulcer, gastric ulcer. , Duodenal ulcer, NSAID (non-steroidal anti-inflammatory drug) -induced ulcer, gastritis, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-diffuse gastroesophageal reflux disease (NERD) ), Visceral pain, chest burn, nausea, esophageal inflammation, swallowing disorders, salivation, airway lesions or asthma.

However, the water solubility of this compound is very low (0.02 mg / ml, pH 6.8), which increases under acidic conditions (0.7 mg / ml, pH 3.0), but is not sufficient to exert excellent effects. Absent. The compound is insoluble in water and has very low solubility, especially in neutral or higher pH environments. Therefore, it is very difficult to formulate it in a pharmaceutical product by dissolving and stabilizing it in an aqueous solution. Also, the increase in decomposition products under acidic conditions results in poor stability and limited salt selection. Furthermore, when a solubilizer such as a surfactant is used to improve the solubility, an excessive amount of excipient is required, which causes difficulty.

In order to develop a drug having a very low water solubility, which comprises the compound represented by the above formula 1, as an injectable composition, an excess amount of a solubilizer and an organic solvent are generally required. However, in the case of a pharmaceutical composition containing a large amount of a solubilizer and an organic solvent, there is a problem that hypersensitivity may occur when a high dose of such a component is administered.

For example, the well-known poorly water-soluble drug docetaxel is solubilized by using a highly viscous polysorbate. In this case, it is difficult to perform the 0.22 μm filtration step, which is indispensable for the preparation of the injectable preparation, which causes a problem during the preparation. Furthermore, there is also a problem that a hypersensitivity reaction may occur due to the large amount of polysorbate used.

International Patent Publication WO99 / 24073 discloses that certain cyclodextrins are used to increase the water solubility of docetaxel. In this patent document, docetaxel is dissolved in a small amount of ethanol, acetyl γ cyclodextrin (Ac-gamma-CD) or hydroxypropyl β cyclodextrin (HP-beta-CD) is added, and the resulting mixed solution is aqueous. Includes a step of dissolving in a solvent. Also disclosed is a method of removing ethanol from the solution obtained above and lyophilizing the obtained residue to prepare a lyophilized composition. However, according to the above patent document, docetaxel is solubilized using a very large amount of cyclodextrin, which results in a large amount of lyophilized product, very low commercial productivity, and in addition. There is a drawback in that the ethanol used to dissolve docetaxel is also very likely to remain.

In addition, European Patent Office 2,409,699 describes a composition containing hydroxypropyl-β-cyclodextrin (HP-beta-CD) and glycine in order to stabilize voriconazole, which is a drug having low water solubility. However, it is inadequately effective in maintaining stability under long-term acceleration or stress conditions.

That is, as described above, it is very difficult to develop a drug having low water solubility as a highly soluble preparation that can be practically used as an injection while maintaining excellent stability in many cases.

Therefore, for such compounds, solubilizers such as ethanol and polysorbate, which may have harmful effects as injections, were not used, and the stability was excellent and sufficient solubility was ensured for use as injections. It is required to consider the formulation.

Along this line, with respect to the compound represented by the formula 1, the present inventors have developed a thermodynamically very stable injectable preparation having excellent water solubility and stability at the same time. An attempt was made to complete an injectable composition containing the compound represented by 1.

International Patent Gazette WO99 / 24073
European Patent Office 2,409,699

An object of the present disclosure is an injectable composition comprising a pharmaceutically acceptable salt of a compound represented by the following formula 1 and one or more selected from mannitol, trehalose, lactose and glucose as stabilizers. It is to provide the manufacturing method.

[Equation 1]

As a means for solving the above problems, the present invention comprises a pharmaceutically acceptable salt of the compound represented by the formula 1 and one or more selected from mannitol, trehalose, lactose and glucose as stabilizers. To provide an injectable composition comprising.

In the present disclosure, the compound represented by the formula 1 is a novel substance for preventing and treating gastrointestinal diseases and associated bleeding according to the pharmacological mechanism of potassium competitive acid blocker (P-CAB). .. Since the compound represented by the formula 1 is water-insoluble or poorly water-soluble in a neutral to alkaline environment, it is difficult to develop an injection, and the solubility is relatively high. Since the chemical structural stability is extremely poor in an acid environment, there is a problem of causing an increase in decomposition products. In order to incorporate the compound represented by the formula 1 into the composition for injection, it is necessary to dissolve the compound represented by the formula 1 at the same time while ensuring the stability of the obtained composition.

The present inventors have tried to formulate various preparations in order to develop an injectable composition containing a pharmaceutically acceptable salt of a compound represented by the formula 1 which is a poorly water-soluble drug, and as a result, they are stable. It has been found that if the agent contains one or more selected from mannitol, trehalose, lactose and glucose, its complete solubility and stability to decomposition can be achieved. Further, by simplifying the manufacturing process through the improvement of solubility, the manufacturing efficiency can be improved.

In the present disclosure, the pharmaceutically acceptable salt of the compound represented by the formula 1 includes an acid addition salt. Acid addition salts include, for example, acetate, adipate, asparagate, benzoate, besylate, hydrogen carbonate / carbonate, hydrogen sulfate / sulfate, borate, camsilate, citric acid. Salts, cyclamates, edicylates, esylates, formates, fumarates, gluceptates, gluconates, glucronates, hexafluorophosphates, hybenzates, hydrochlorides / chlorides Things, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactic acid, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2 -Napsilate (2-napsylate), nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate , Saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, xinafoate, pidolate and the like.

In particular, the salt of the compound represented by the formula 1 may be a pidolate represented by the following formula 2.

[Equation 2]

The injectable composition according to the present disclosure may contain one or more selected from mannitol, trehalose, lactose and glucose as stabilizers. They may be in anhydrous or hydrated form. By containing the stabilizer, the composition may have excellent solubility while minimizing the formation of impurities from the pharmaceutically acceptable salt of the compound represented by the formula 1.

The compositions of the present disclosure are prepared prior to the step of lyophilizing the solution and are pharmaceutically acceptable salts of the compounds of formula 1 and one or more selected from mannitol, trehalose, lactose and glucose. And include. In the present disclosure, it is possible to support the process setting by grasping the storage stability before lyophilizing the solution.

The compositions of the present disclosure also include, for example, solutions prepared from lyophilized powders or cakes reconstituted with saline or other pharmaceutically acceptable diluents. The compositions of the present disclosure further comprise a solution obtained in such a way that the reconstituted solution is diluted with a pharmaceutically acceptable diluent.

The injectable composition according to the present disclosure may contain a pharmaceutically acceptable salt of the compound represented by Formula 1 and one or more selected from mannitol, trehalose, lactose and glucose as stabilizers. The content of the stabilizer is 0.5-3.0 parts by weight, particularly 0.7-2.0 parts by weight, based on 1 part by weight of the pharmaceutically acceptable salt of the compound represented by the formula 1. If the stabilizer exceeds 3.0 parts by weight, the viscosity of the solution becomes too high, and as a result, filtration becomes impossible after dissolution, and there is a disadvantage that lyophilization takes too long.

Specifically, the injectable compositions according to the present disclosure are in the form of liquids or dry powders. The dry powder for injection may be administered to the patient to be reconstituted with WFI, saline, glucose solution, amino acid solution and the like.

Drying can be carried out by conventional drying methods, such as lyophilization, spray drying or fluidized bed drying, preferably lyophilization.

In one embodiment of the present disclosure, an injectable composition comprising a pharmaceutically acceptable salt and stabilizer of the compound of formula 1 in an amount of 0.7 to 2.0 parts by weight with respect to 1 part by weight of the compound. In the case, it was confirmed that the stability of the composition could be maintained under stress conditions without any change in its properties and without a sharp increase in its total impurities and individual impurities.

According to the present disclosure, the pH of the injectable composition ranges from 3.0 to 5.0, particularly 3.5 to 4.5. When the pH of the injectable composition is 3.0 or less, the decomposition products of the active ingredient increase. When the pH is 5.0 or less, there is a problem that the content of the active ingredient in the composition decreases. The pH can be adjusted by adding a pH adjuster to the composition or the like. Here, conventional pH regulators used to regulate the pH of the composition when preparing the composition for injection, such as hydrochloric acid, sodium hydroxide and the like, can be used without limitation.

In one embodiment of the present disclosure, an injection having a different pH comprising a pharmaceutically acceptable salt of the compound of formula 1 and one or more selected from mannitol, trehalose, lactose and glucose as a composition. As a result of analyzing the stability of the composition for use, the composition having pH 3.0 to 5.0 did not change in the properties of the composition, the total amount of impurities was small, and the content of the compound of Formula 2 was stable during the storage period. It was confirmed that it was maintained. On the other hand, compositions with a pH of 2.0 or less showed an increase in impurities and a decrease in the content of the compound of formula 2 during the same period.

Similarly, the injectable compositions of the present disclosure can ensure the solubility required to compose the injectable composition and contain one or more selected from mannitol, trehalose, lactose and glucose, pH. Is adjusted to the range of 3.0 to 5.0 and has the advantage of being able to be stably stored for a long period of time.

The amount of the active ingredient contained in the injectable composition of the present disclosure varies depending on the condition of the patient to be administered, the degree of targeted treatment, and the like. Preferably, the compositions of the present disclosure may be contained at a concentration of 1 to 200 mg / ml, preferably 1 to 50 mg / ml, based on the compound of formula 1. When the active ingredient is contained in a low concentration of 1 mg / ml or less, a large amount of injectable solution is required to exert a sufficient therapeutic effect, which makes it difficult to administer to the affected area of the patient. If it contains a high concentration of 200 mg / ml or more, it is difficult to satisfy the composition in which even the stabilizer dissolves, and precipitation or impurities may occur during resuspension or dissolution. There is.

WFI may be used in preparing the injectable composition according to the present disclosure. Injections containing pharmaceutically acceptable salts of the compounds of formula 1 according to the present disclosure do not necessarily include additives other than stabilizers and pH regulators, but are more conventionally used in the art. The isotonic agent, the buffer solution, the penetrant, and the like may be arbitrarily contained without being limited to these.

The injectable composition of the present disclosure can be usefully used as an injection because the active ingredient can be completely dissolved, the generation rate of impurities is very low, and the composition can be stored for a long period of time.

^{The results of 1} H-NMR of the compound represented by the formula 2 prepared according to one embodiment of the present disclosure are shown.

Hereinafter, in order to better understand the present disclosure, the following will be described in detail with reference to preferred examples. However, the following examples are provided for purposes of exemplifying the present disclosure only, and thus the present disclosure is not limited thereto.

Preparation of pidolate represented by the formula 2

After 100 g of the crystalline compound of formula 1 and L-pyroglutamic acid (34.98 g, 1.05 eq) were completely dissolved in 1000 ml of methanol, the mixture thus prepared was placed under reduced pressure until solids precipitated. Concentrated with stirring at 50 ° C. A co-solvent, which is a mixture of acetone / ethyl acetate = 1/4 (500 ml), was added to the obtained concentrate at 25 ° C., and the mixture was vigorously stirred for 30 minutes. Then, the solid was filtered under reduced pressure, washed with ethyl acetate (100 ml), and the obtained solid was vacuum dried at 40 ° C. for 16 hours to 113.8 g (yield 85.4%) of the amorphous compound represented by the formula 2. Was obtained as a white powder (Fig. 1).

[Examples 1 to 9] Identification of the characteristics of the compound for injection when mannitol is added and the total amount of impurities in the compound.

The compound represented by the formula 2 (1000 mg) was dissolved in WFI (50 ml) to prepare a bulk solution. After dissolving a part (5 ml) of a solution containing about 100 mg of the main component (compound represented by the formula 2) in a 20 ml vial containing 100 mg of mannitol, 1.0 N HCl was prepared above. The pH was adjusted to 2.0, 2.5, 3.0, and 4.0, respectively, by adding to each of the prepared mixtures. A portion of the bulk solution was placed in an empty 20 ml sample vial without pH adjustment and all prepared solutions were lyophilized. Freeze-drying was performed using a freeze-dryer. After the lyophilization was completed, the lyophilized sample was left in a chamber at 60 ° C. / 80% relative humidity for 4 weeks. The sample was then analyzed by HPLC and stability evaluated based on the total amount of impurities produced during the storage period. The analytical conditions for measuring the content of impurities are as follows.

Column: Column filled with octadecyl silica gel for liquid chromatography

Column temperature: Constant temperature of about 30 ° C

Detector: UV absorptiometer (measurement wavelength: 220 nm)

Flow rate: 0.8 mL / min

Mobile phase gradient condition

As shown in Table 1 below, the results are shown in terms of the peak area (%) of total impurities relative to the total area of the peaks.

In Example 1 in which only the main component was freeze-dried, the total amount of impurities (%) was 0.42%, indicating that the stability was extremely poor. On the other hand, in Example 2 of the present invention, the total amount of impurities was 0.17%, indicating a significant improvement in stability. Observation of pH-dependent changes in total impurities showed that the lower the pH, the greater the amount of impurities, that is, the smaller amount of total impurities generated between pH 3.0 and 5.0. ..

In addition, experiments were conducted under different pH conditions in the same manner as in Examples 1 to 5 above.

To prepare the composition for injection, a compound represented by the formula 2 (1000 mg) was dissolved in WFI (50 ml) to prepare a bulk solution. In the same manner as in Example 1, 1.0N NaOH was added to a solution containing the main component (about 100 mg) and 100 mg of mannitol to adjust the pH to about 4.5, 5.0, 5.5, and 6.0, and then Christi Epsilon. All samples were dried using a 2-10D freeze dryer. The lyophilized sample was left in a chamber at 60 ° C. / 80% relative humidity for 4 weeks, and after storage was completed, the impurities were analyzed by HPLC, and the results are shown in Table 2. After storage for 4 weeks, the lyophilized cake was reconstituted with physiological saline at a concentration of 10 mg / ml and then stored at room temperature.

As a result of identifying such characteristics after reconstruction, it was demonstrated that the sample after reconstruction has a transparent property with a small amount of total impurities at a pH of 5.0 or less.

[Examples 10 to 11] Specifying the total amount of impurities in the injectable composition according to the type and amount of the stabilizer

A solution was prepared by dissolving the compound represented by the formula 2 (1000 mg) in WFI (50 ml). After dissolving a part (5 ml) of a solution containing about 100 mg of the main component in a vial containing 100 mg of mannitol or 100 mg of trehalose, all the prepared solutions are lyophilized without pH adjustment. Dryed by. Then, the prepared lyophilized sample was left in a chamber at 60 ° C. / 80% relative humidity for 4 weeks. The samples were then analyzed by HPLC and the results are summarized in Table 3 showing the results of the major degradation products for each cake.

The results of Examples 10 and 11 demonstrated a significant improvement in the stability of the principal components and compounds containing mannitol, trehalose, lactose, or glucose.

However, in the case of an injectable composition containing 50 mg of mannitol or trehalose under the same conditions, the amount of total impurities increased significantly due to the low content of the stabilizer. Further, when mannitol or trehalose is contained in a high weight of 300 mg or more, the volume becomes too large, and there is a disadvantage that it takes time to prepare the composition by the freeze-drying method.

[Example 12-17] Identification of characteristics of injectable composition and content of total impurities

A solution was prepared by dissolving the compound represented by the formula 2 (1000 mg) in WFI (50 ml). A portion (5 ml) of a solution containing 100 mg of the main component was dissolved in each vial containing 100 mg of mannitol or 100 mg of trehalose, followed by 1.0N HCl and 1.0N NaOH, respectively. The pH was adjusted to 2.0, 4.0, and 6.0, and freeze-dried. Then, the obtained lyophilized sample was left in a chamber at 60 ° C. / 80% relative humidity for 4 weeks. After storage in this way, the samples were analyzed to determine their total impurities after reconstruction and trends in their properties.

As shown in Table 4, in the case of the compositions of Examples 13, 14, 16 and 17 of the present disclosure, it can be seen that the total amount of impurities remains constant even if the pH changes. However, when preparing a pH 6.0 composition, it proved to be inappropriate because the composition became opaque after reconstitution. In the case of Examples 12 and 15, it can be seen that the amount of impurities is increased due to the influence of pH 2.0. From the above, in the case of a formulation containing mannitol, trehalose or both, and having a pH in the range of 3.0 to 5.0, the appearance of the cake can be maintained during storage, and the solubility at the time of reconstruction is also high. It can be seen that it is a highly stable preparation that can be maintained, has no change in its contents, and produces less impurities.

Although the specific parts of the present disclosure have been described in detail above, such detailed description is given only for the purpose of showing exemplary embodiments, and does not limit the scope of the present disclosure. It is obvious to those skilled in the art. It will therefore be appreciated that the substantive scope of the present disclosure is defined by the appended claims and their equivalents.

Claims (19)

And pharmaceutically acceptable salts of the compounds of formula 1 below, contain one or more and the selected mannitol and trehalose or found as a stabilizer,
The composition is in liquid form, and
An injectable composition, characterized in that the pH of the injectable composition is in the range of 3.0 to 5.0 .
[Equation 1]

The injectable composition according to claim 1, wherein the pharmaceutically acceptable salt of the compound represented by the formula 1 is the compound represented by the following formula 2.
[Equation 2]

The injectable composition according to claim 1, wherein the stabilizer is mannitol or trehalose. The injectable composition according to claim 1, wherein the stabilizer is present in an amount of 0.5 to 3.0 parts by weight based on 1 part by weight of a pharmaceutically acceptable salt of the compound represented by the formula 1. The injectable composition according to claim 1, wherein the injectable composition is for lyophilization. The injectable composition according to claim 1, wherein the composition further comprises one or more selected from isotonic agents, buffers, penetrants and pH regulators. The injectable composition according to claim 2, wherein the stabilizer is mannitol or trehalose. The injectable composition according to claim 2, wherein the stabilizer is present in an amount of 0.5 to 3.0 parts by weight based on 1 part by weight of a pharmaceutically acceptable salt of the compound represented by the formula 1. Set Narubutsu is for lyophilized injectable composition of claim 2. The injectable composition according to claim 2, wherein the composition further comprises one or more selected from isotonic agents, buffers, penetrants and pH regulators. A dry powder containing a pharmaceutically acceptable salt of the compound represented by the following formula 1 and one or more selected from mannitol and trehalose as stabilizers.
[Equation 1]

The dry powder according to claim 11, wherein the pharmaceutically acceptable salt of the compound represented by the formula 1 is the compound represented by the following formula 2.
[Equation 2]

The injectable composition according to claim 11 or 12, wherein the stabilizer is present in an amount of 0.5 to 3.0 parts by weight based on 1 part by weight of a pharmaceutically acceptable salt of the compound represented by the formula 1. The dry powder according to claim 11 or 12, wherein the stabilizer is mannitol or trehalose. The dry powder according to claim 11 or 12, further comprising one or more selected from isotonic agents, buffers, penetrants and pH regulators. The dry powder according to claim 11 or 12, which is for injection. The dry powder according to claim 16, which is administered so as to be reconstituted with a pharmaceutically acceptable diluent. The dry powder according to claim 16, which is reconstituted with a pharmaceutically acceptable diluent. The dry powder according to claim 17 or 18, which is reconstituted with WFI (water for injection), physiological saline, glucose solution or amino acid solution.

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